Adipose tissue or body fat is loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells (i.e. adipose tissue macrophages (ATMs)). Adipose tissue is derived from preadipocytes. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body. However, excessive accumulation of fat in adipose tissue is undesirable and may lead in first instance to aesthetic problems but ultimately also to pathological conditions such as obesity, lipid storage disease (in particular hepatic steatosis) and hyperlipemia.
The invention relates to the use of dipeptidyl ketoamide compounds for preventing accumulation of triglycerides in adipose tissue or for reducing the amount of triglycerides in adipose tissue in a subject in need thereof. Prevention of triglyceride accumulation and reduction of the amount of triglycerides in adipose tissue allows the use of the dipeptidyl ketoamide compounds of the invention to control weight gain, and/or to treat an obesity-related condition selected from the group consisting of obesity, lipid storage disease (in particular hepatic steatosis) and hyperlipemia.
Thus, the invention also relates to a i) non-therapeutic method for reducing fat accumulation in a subject which does not suffer from obesity or other obesity-related conditions such as lipid storage disease (in particular hepatic steatosis) and hyperlipemia by administration of certain dipeptidyl ketoamide compounds, ii) the use of said dipeptidyl ketoamide compounds for preventing and/or treating an obesity-related condition selected from the group consisting of obesity, lipid storage disease (in particular hepatic steatosis) and hyperlipemia and iii) said dipeptidyl ketoamide compounds for use in preventing and/or treating an obesity-related condition selected from the group consisting of obesity, lipid storage disease (in particular hepatic steatosis) and hyperlipemia.
Obesity is excess body weight for a particular age, sex and height as a consequence of imbalance between energy intake and energy expenditure. The primary cause of obesity is either due to overeating, inadequate exercise or eating disorder, some genetic disorders, underlying illness (e.g., hypothyroidism), certain medications, sedentary lifestyle, a high glycemic diet (i.e., a diet that consists of meals that give high postprandial blood sugar) weight cycling (caused by repeated attempts to lose weight by dieting, eating disorders), stress and insufficient sleep.
A common indication of a person's overweight is the body mass index (BMI) which is a measure of relative weight based on an individual's mass and height and is defined as the individual's body mass divided by the square of their height—with the value universally being given in units of kg/m2.
It is generally accepted within the medical profession that a person does not have overweight if he has a BMI not higher than 25 kg/m2. On the other side when a person's BMI exceeds a value of 30 kg/m2 it is generally accepted that said person is suffering from obesity. Between 25 kg/m2 and 30 kg/m2 the person is considered to have overweight.
Obesity is characterized as uncontrolled adipose tissue mass in the body and recognized as the fastest growing metabolic disorder in the world. An increase in adipose tissue mass can be the result of the production of new fat cells through the process of adipogenesis and/or the deposition of increased amounts of cytoplasmic triglyceride or lipid droplets per cell. Adipogenesis is the process of cell differentiation by which preadipocytes become adipocytes. In the adipogenesis process, proliferation of preadipocytes or precursor fat cells needs to be followed by the differentiation of these cells to the mature adipocyte phenotype. Increased lipid accumulation in the mature adipocyte cells is the most important feature of obesity disorder.
Fat is stored as triglycerides form in adipose tissue. Reducing the formation of new adipose tissue and formation of fat reserves through inhibition of differentiation of pre-adipocytes into mature adipocytes may be a good strategy to control adipogenesis mediated diseases, especially obesity. Modulation of adipogenesis in humans may thus lead to a reduction in the burden of obesity.
Low-caloric diets and exercise may help with weight loss; however, diet and exercise alone have not proven successful for long-term solutions in weight management. In addition, supplementation with drugs that suppress appetite, reduce food intake, reduce dietary fat absorption, increase energy expenditure and effect nutrient partitioning or metabolism have potential efficacy but they are unfortunately accompanied by adverse side effects (C. A. Haller and N. L. Benowitz., New England J. Medicine, 2000, 343, 1833-1838). Several drugs have been prescribed for the treatment of obesity (M. K. Sharma et al., European Journal of Medicinal Chemistry, 2014, 79, 298-339). One such drug, is phentermine (Fastin, Adipex P), which is prescribed for short term use in weight control. However phentermine has side effects such as high blood pressure, headache, insomnia, irritability and nervousness. Another drug for weight control is Orlistat (marketed as Xenical® by Roche and as Alli® by GlaxoSmithKline). A number of undesirable side effects have also been reported for Orlistat: gas generation, cramps, diarrhoea and elevated blood pressure.
Thus, the need exist to find new drugs to be used in anti-obese therapy.